The control of glucose production is one of the key aspects of anti-diabetic therapy. Type 2 diabetics have elevated levels of postprandial and fasting blood glucose (Consoli, A., Nurjhan, N., Capani, F. and Gerich, J. Diabetes 38, 550–7, 1989; Shulman, G I Am. J. Card. 84(Suppl.1A):3J-10J, 1999). Excessive hepatic glucose production (HGP) contributes to the fasting hyperglycemia observed in patients with Type 2 diabetes (T2D) (Gastadelli, A., Baldi S., Pettiti M., Toschi, E., Camastra, S., Natali, A., Landau, B. R. & Ferranini, E., Diabetes 49:1367–1373, 2000. Gluconeogenesis is believed to be the major pathway for this increased glucose production (Defronzo, R. A., Bonadonna, R. C. and Ferrannini, E., Diabetes Care 15:318–367, 1992).
Phosphoenolpyruvate carboxykinase (PEPCK) is a key regulatory enzyme in the gluconeogenic pathway. PEPCK is believed to be the flux controlling, rate limiting enzyme for this pathway (Cimbala, A. N., Lamers, W. H., Nelson, J. E., Monahan, J. E., Yoo-Warren, H., and Hanson R. W., J. Biol. Chem. 257:7629–7636, 1982), hence inhibition of this enzyme represents a novel way to improve glucose homeostasis. Previously, attempts to control hepatic glucose production through inhibition of gluconeogeneis were limited to biguanides such as metformin (Defronzo, R. A., Diabetes Reviews 6:89–131, 1998). Metformin inhibits HGP, but by an unknown mechanism. In addition, it has side effects such as gastrointestinal (GI) disturbances and lactic acidosis. Inhibition of PEPCK provides superior efficacy and, coupled with reduced side effects, represents a novel treatment for type 2 diabetes.